The present invention pertains to medical devices and methods for the treatment of cardiac disorders by delivering a therapeutic protein formulation to the pericardial sac region of the heart.
Deoxyribonucleic acid, or DNA, contains the hereditary information passed onto all offspring. The sequential information contained in DNA is used to guide the synthesis of other molecules called proteins, which are long unbranched polymer chains of amino acids. A gene is defined as the segment of DNA sequence corresponding to a single protein. Proteins are the primary functional unit of human cells and have a host of functions including catalyzing reactions (enzymes), maintaining structure, generating movement, and sensing signals. Each protein performs a specific function according to its genetically specified sequence of amino acids. Genetic mutations can lead to mutations in the amino acid sequence of the associated protein that, in turn, can lead to inadequate or abnormal function of the protein. These modifications of proteins can cause major illness and disease.
A gene mutation can be inherited from parents or caused by a number of factors including environmental agents such as radiation, chemicals, and viruses. As a consequence of the gene mutation, the corresponding mutated protein is absent or deficient in its level of activity, loses its ability to regulate cellular processes, or has a nonfunctional structure. These protein deficiencies are known to be the cause of many diseases, including many cardiac diseases. One category of cardiac diseases is inborn errors of metabolism, which includes amino acidopathies, urea cycle defects, lysosomal storage disorders, and fatty acid oxidation defects. Using lysosomal storage diseases as an example, the protein (enzyme) deficiency results in the toxic accumulation of substrates at the point of the blocked metabolic path, accumulation of toxic intermediates from an alternative pathway, or toxicity caused by a deficiency of products beyond the blocked point. The degree of metabolic deficiency, which is related to the degree of protein deficiency, is a major factor in the clinical manifestation (phenotype) and severity of the disease. Many of these protein deficiency diseases have an effect on cardiac cells (See Table 1).
One focus for treating protein deficiency diseases has been to administer the missing enzyme to the patient suffering from the corresponding enzyme deficiency. Such enzyme replacement therapy (ERT) can be accomplished by administering an isolated or synthetic form of the enzyme (e.g. a recombinant protein) to the patient. Intravenous or other systemic administration of an enzyme as ERT can be effective in treating some disease symptoms. ERT has been especially effective in diseases, such as Gaucher Disease, which primarily affects the liver and spleen, because the proteins are quickly taken-up from the bloodstream by these organs.
Other lysosomal storage diseases are not treated adequately with ERT because of the limited take-up of the proteins by the effected organ or tissue.
ERT is not as effective in treating cardiac aspects of Pompe Disease, a lysosomal storage disease, because of the large mass of the heart and the difficulty of this large mass of tissue taking-up the replacement enzymes in the short time these enzymes are available in the bloodstream. This traditional type of ERT can therefore be costly and ineffective due to the mass amounts of enzyme needed, the possibility of poor results due to the enzyme uptake by other organs, and failure of the cardiac cells to import the enzyme once received.
One way of addressing the problems of delivery of the deficient enzyme to the heart cells of patients suffering from these diseases is by gene therapy.
Gene therapy for cardiac disorders involves genetically engineering the DNA coding sequence for the deficient enzyme into a non-viral or viral vector, then surgically injecting the vector into the heart, after which the cells transfected by the vector produce the missing enzyme and may secrete it to adjacent tissues. See Kmiec, Gene Therapy, American Scientist, 87 (3): 240 (1999). To date, although this approach has been demonstrated to be feasible in animal models, it has not yet been proven effective in treating cardiac disorders in humans.
There have also been attempts to treat patients with enzyme deficient diseases by providing the needed enzymes through bone marrow transplants. See Hsu et al., Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation,” Bone Marrow Transplantation, 24:103-107 (1999); Yeager et al., “Bone marrow transplantation for infantile ceramidase deficiency (Farber disease),” Bone Marrow Transplantation, 26:357-363 (2000). Such attempts are based on the premise that undifferentiated stem cells originating from implanted bone marrow will develop into and replace the genetically defective cardiac cells that cause a particular cardiac disorder. While this type of therapy may be effective in some diseases, the high morbidity associated with this procedure has prevented its widespread use in all but a few of the most serious diseases.
Another way of addressing delivery of the deficient enzyme to the heart is by direct “manual” injection or injection into the blood stream so the therapeutic compound can find its way into the heart. Based upon the results, this type of remedy still does not overcome the inefficiencies of cellular uptake of the enzyme. Even if effective, systemic delivery would require the repeated administration of large amounts of expensive enzymes with only a small percentage of these enzymes ultimately reaching the area of the heart that is targeted.
Additionally, a potential problem in the treatment of cardiac diseases is the possibility of toxic build-up and serious side effects of downstream metabolic byproducts upon initial treatment with the missing enzyme. This occurs when the sudden availability of the missing enzyme, and the presence of the accumulated substrate for it, results in the rapid production of downstream metabolic byproducts of the previously blocked step, overwhelming the ability of the enzymes in the downstream pathways to perform their downstream steps. As a consequence, other metabolic intermediates can temporarily accumulate to levels sufficient to cause cardiac damage.
Thus, methods, devices, and systems for delivering enhanced proteins and enzymes to the heart at precise levels for long-term therapies remain an elusive challenge.